Pemphigus vulgaris (PV) is an autoimmune disease with involvement of skin and mucous membrane blistering, which is sometimes fatal, and is histologically characterized by blistering in the epidermis as well as immunopathologically characterized by the presence of autoantibody IgG to the cell surface of keratinocyte (Stanley, J. R. Pemphigus. In Dermatology in General Medicine. I. M. Freedberg, A. Z. Eisen, K. Wolff, K. F. Austen, L. A. Goldsmith, S. I. Katz, and T. B. Fitzpatrick, eds. McGraw-Hill, New York, 654–666 (1998)). Patients with pemphigus vulgaris clinically manifest diffuse flaccid blister and erosion. These can be formed in all the stratified squamous epithelia. Without appropriate therapy, the widespread lesions on the skin result in the leakage of body fluid or secondary bacterial infection, and as a result pemphigus vulgaris may be fatal. The prognosis of pemphigus can be improved by systemic administration of corticosteroid and immunosuppression therapy, but the mortality remains considerably high because of death due to complications caused by the therapy.
The target antigen for pemphigus vulgaris was first identified as a 130 kD glycoprotein through immunoprecipitation of keratinocyte extract (Stanley, J. R. et al., J. Clin. Invest. 70:281–288 (1982); Stanley, J. R. et al., J. Clin. Invest. 74:313–320 (1984)). Then, cDNA for the pemphigus vulgaris antigen was isolated via immuno-screening of a human keratinocyte expression library using affinity-purified autoantibody specific to the pemphigus vulgaris antigen (Amagai, M. et al., Cell 67:869–877 (1991)). Nucleotide sequence analysis has revealed that the pemphigus vulgaris antigen belongs to the superfamily of genes for cadherins that are intercellular adhesion molecules. The pemphigus vulgaris antigen is a membrane protein located in desmosome (Karpati, S. et al., J. Cell Biol. 122:409–415 (1993)), and it was named desmoglein 3 (Dsg3) (Amagai, M. Adv. Dermatol. 11:319–352 (1996)).
There is much evidence showing that autoantibody IgG against Dsg3 protein plays a pathogenic role in pemphigus vulgaris. Firstly, it has been reported that activity of the disease correlates to the antibody titer in blood over time by indirect fluorescent antibody technique (Sams Jr, W. M. & Jordon, R. E., Br. J. Dermatol. 84:7–13 (1971)) or ELISA (Ishii, K., et al., J. Immunol. 159:2010–2017 (1997); Amagai, M., et al., Br. J. Dermatol. 140:351–357 (1999)). Secondly, a newborn from the mother affected with pemphigus vulgaris is also transiently affected with the disease due to the IgG transferred across the placenta from the mother (Merlob, P. et al., Pediatrics 78:1102–1105 (1986)). As the IgG derived from the mother is catabolized, the symptom is remitted. Thirdly, the IgG derived from patients with pemphigus vulgaris can induce blistering in tissue-cultured skin in the absence of complement and inflammatory cell (Schiltz, J. R., & Michel, B., J. Invest. Dermatol. 67:254–260 (1976); Hashimoto, K. et al., J. Exp. Med. 157:259–272 (1983)). Fourthly, passive transfer of the IgG derived from sera of patients into newborn mice causes intraepidermal blister formation with typical histological characteristics (Anhalt, G. J. et al., N. Engl. J. Med. 306:1189–1196 (1982)). Fifthly, depletion of patient-derived serum by immuno-absorption using recombinant Dsg3 protein (rDsg3) comprising extracellular domain thereof removes pathogenicity of the serum and inhibits blistering in newborn mice (Amagai, M. et al., J. Clin. Invest. 94:59–67 (1994)). Finally, antibody affinity-purified with rDsg3 exhibits pathogenicity and thus results in the formation of blister with histological characteristics of pemphigus vulgaris in newborn mice (Amagai, M. et al., J. Clin. Invest. 90:919–926 (1992); Amagai, M. et al., J. Clin. Invest. 102:775–782 (1998)).
Based on these studies, pemphigus vulgaris is one of the best-characterized autoimmune diseases with respect to the processes after the generation of autoantibody in particular. Thus pemphigus vulgaris is now an excellent disease model for tissue-specific autoimmune diseases to study cellular mechanisms underlying the production of autoantibody or destruction of self-tolerance, as well as to develop therapeutic methods specific to the diseases. As the first step toward the goals, it is demanded to develop active disease animal model for pemphigus vulgaris. 
Most of experimental autoimmune disease animal models are provided by repeated injection of autoantigen with a variety of adjuvants. However, as exemplified by the case of myasthenia gravis, in which the frequency of generation of the active disease in mice immunized with acetylcholine receptor (T. californica) varies considerably depending on the strains, the success of this method is thus highly empirical (Berman, P. W. et al., Ann. N.Y. Acad. Sci. 377:237–57 (1981)).
Previously, an in vivo experimental model for pemphigus vulgaris was developed by the reconstruction of severe combined immunodeficiency (SCID) in mice using PBMC derived from patients with pemphigus vulgaris (Juhasz, I. et al., J. Clin. Invest. 92:2401–7 (1993)). With this model, lymphocytes from the patients produced circulating autoantibody at a low titer, but it was rare that active intraepidermal blistering with deposition of human IgG was found in mouse skin. When human skin was transplanted on SCID mouse, blisters similar to those in pemphigus vulgaris were recognized on the transplanted skin. However, it cannot be denied that the cause of blister formation in this model is an inflammatory response due to the tissue incompatibility with human PBMC and skin. Thus there was no established active disease model for pemphigus vulgaris. 